1. Field of the Invention
This invention relates generally to medical devices intended for implantation into humans. More particularly, this invention concerns methods for providing medical devices which can inhibit microbial infection and thrombogenesis on or near the medical device after its implantation into the body.
2. Description of the Related Art
Implantable medical devices have become critical in the management of a variety of human diseases and other conditions. Colonization of microorganisms on the surfaces of such medical devices following implantation occurs relatively infrequently, but can produce serious and costly complications, including the need to remove and/or replace the implanted device and/or vigorous treatment of secondary infections.
Although infection of implanted medical devices is a relatively infrequent complication associated with their clinical use, the threat to infected patients, and the cost to the medical care system, are significant. For example, in heart valve replacement surgery, one of the most serious complications is prosthetic valve endocarditis (PVE). Prosthetic valve endocarditis is a result of bacterial infection at the junction of the sewing cuff and annulus, or in the valve sewing cuff itself. Although the overall frequency of PVE is only about 1% per patient year, the condition is associated with high morbidity and mortality (up to 60%).
Approaches for controlling infections associated with implanted medical devices have had only limited success. For example, although coating a material with immobilized antimicrobial compounds has been reported to effectively reduce bacterial colonization of devices in a laboratory setting, similar results have been difficult to replicate in the clinical setting. To be effective in vivo, antimicrobial agents immobilized on the surface of a medical device need to intimately contact the colonizing bacteria that has infected the device. Unfortunately, many clinically relevant bacteria produce a slimy protective substance called biofilm within which they grow. This biofilm, among other things, prevents direct contact of the bacterial cells with a substrate surface to which they adhere, making the bacteria resistant to otherwise toxic materials that may be present on the substrate surface.
In the laboratory, the antimicrobial efficacy of medical devices that have been treated in one way or another in attempt to confer some degree of antimicrobial activity to the device, has often been evaluated by exposing the devices to bacterial cultures. The selection and source of bacteria for such testing is critical to obtaining meaningful results, since it is now known that microorganisms floating free in a cell culture (called planktonic bacteria) behave differently than those adherent to a substrate, such as a bacterial culture vessel or an implanted medical device. Planktonic bacteria are more susceptible to antimicrobial agents immobilized on a surface than are biofilm-producing bacteria. Thus, devices coated with immobilized antimicrobial agents may effectively prevent colonization of planktonic bacteria in the laboratory, but may be completely ineffective in preventing infection of devices by clinically relevant biofilm-enclosed bacteria. As a result, the experimental use of planktonic bacteria cultured in the laboratory, rather than biofilm bacteria derived from clinical infections, has led to the commercialization of numerous medical devices lacking clinical efficacy.
To effectively inhibit biofilm bacterial growth, an antimicrobial agent should penetrate the biofilm. To achieve this, the antimicrobial agent must be able to diffuse from the surface of the medical device following implantation. Therefore, antimicrobial agents immobilized on the surface of a medical device, and therefore not subject to diffusion, are largely ineffective against many clinically relevant microorganisms. A more effective medical device will have the ability to deliver diffusable antimicrobial agent to the local environment following implantation.
Various methods have been described for coating or otherwise incorporating antimicrobial agents into or onto medical devices in a manner which allows for their release into the local environment of an implanted medical device. U.S. Pat. No. 5,624,704 reports a method for impregnating a non-metallic medical implant with an antimicrobial agent by first dissolving the antimicrobial agent in an organic solvent to form an antimicrobial composition. Thereafter, a separate penetrating agent and alkalinizing agent must be added to the antimicrobial composition. The antimicrobial composition is then applied to a medical device of interest in order to cause the incorporation of the composition into the material of the medical device. Thus, the method of U.S. Pat. No. 5,624,704 teaches the necessity of using additional components, i.e., penetrating and alkalinizing agents, in a dissolved antimicrobial composition, in order to achieve effective incorporation into the medical device. Unfortunately, the use of these additional components can substantially increase the materials and processing costs associated with such a method, and can also lead to degradation of the antimicrobial agents.
In addition to the problems of microbial infection discussed above, other complications associated with the use of many implantable medical devices stem from the complex cellular and humoral reactions which occur when a foreign material comes into contact with blood and/or other physiological fluids. Among the most significant of these are the rapid thrombogenic actions which can occur following implantation of a medical device. Initial contact of a device with blood results in deposition of plasma proteins, such as albumin, fibrinogen, immunoglobulin, coagulation factors, and complement proteins. The cellular activities which follow can, among other things, lead to vascular constriction which can hinder blood flow, and inflammatory reactions which can damage or impair the function of a medical device. A variety of methods and compositions have been reported for increasing the thromboresistance of medical device surfaces by bonding or incorporating into or onto the device one or more antithrombogenic agents, such as heparin, hirudin, albumin, phospholipids, streptokinase, tissue plasminogen activator (TPA) or urokinase, hydrophilic polymers such as hyaluronic acid, chitosan, methyl cellulose, and poly(ethylene oxide), poly(vinyl pyrrolidone), growth factors such as endothclial cell growth factor, epithelial growth factor, osteoblast growth factor, fibroblast growth factor, platelet derived growth factor (PDGF), and angiogenic growth factor, and other proteins, carbohydrates and fatty acids.
The present invention is directed to providing medical devices which have both antimicrobial and antithrombogenic properties for overcoming, or at least reducing the effects of, one or more of the problems set forth above.
According to one aspect of the present invention, a method is provided for producing a medical device having antimicrobial and antithrombogenic properties. The method, in a first treatment process, comprises dissolving one or more antimicrobial agents in a suitable solvent, such as an alcohol, ether, aldehyde, acetonitrile, or combinations thereof, to form an antimicrobial solution. The antimicrobial solution is thereafter contacted with at least a portion of a medical device under conditions effective for causing incorporation of the antimicrobial agent into or onto the portion of the medical device contacted by the antimicrobial solution. The method further comprises a second treatment process, which may be performed before, after, or in some situations simultaneous with, the first treatment process described above, wherein the medical device is treated in a manner that provides an antithrombogenic agent or material in or on at least a portion of the medical device. As a result, the portion of the medical device so treated exhibits antithrombogenic properties, i.e., has a reduced propensity for eliciting a thrombogenic response following implantation of the device, compared with a similar device which has not been subjected to the antithrombogenic treatment.
The incorporation of the antimicrobial agent into or onto the medical device is advantageously achieved without the need for additional components in the antimicrobial solution, i.e., penetrating agents, alkalinizing agents, etc., in order to achieve incorporation of the antimicrobial agent into or onto the device. The antimicrobial agent incorporated into a medical device according to this invention nonetheless exhibits clinically desirable antimicrobial release kinetics from the medical device after exposure to an in vivo environment.
In yet a further aspect of the present invention, medical devices are provided which have antimicrobial and antithrombogenic agents and/or materials present on at least some portion of the devices. Consequently, the medical devices provided by this invention are less susceptible to microbial colonization and thrombogenic activity following implantation of the devices in vivo.